Opioid analgesics, such as morphine, are irreplaceable strong analgesics which have been widely used in clinical practice. Data shows that a total of 230 million prescriptions of opioids were written out just in the year 2007 in the US. Opioids mainly act on opioid receptors. Opioid receptors include three types, μ-, δ- and κ-receptors, each includes various subtypes. Opioid receptors exist in central nervous system such as spinal cord as well as peripheral nerves in stomach, small intestine, exocrine glands and the like. Therefore, opioid analgesics, having strong analgesic effects on central nervous system, lead to side effects by acting on peripheral opioid receptors. Primary side effects include opioid-induced bowel dysfunction and constipation. For patients suffering from chronic pain, in particular, these side effects always affect their quality of life due to chronic administration of opioids for pain relief.
Naloxone (structural formula I) is a derivative of oxymorphine, and is a specific antagonist of opioid receptors, having competitive antagonistic effects on various types of opioid receptors in vivo. It binds to opioid receptors in vivo to counteract excessive release of β-endorphins. The in vivo absorption and metabolism of naloxone are rapid; and the antagonistic effects thereof are strong. It can pass through blood-brain barrier easily, and bind to the receptors in place of morphine-like substances, thereby relieving CNS inhibition and recovering normal functions of organs such as brain, heart, and lungs rapidly without the occurrence of drug dependence, withdrawal symptoms and respiratory depression as in the case of morphine-like substances. Naloxone is a specific antidote for morphine overdose as well as a diagnostic agent for morphine and heroin addicts. Recent domestic and foreign clinical trials of naloxone for the treatment of acute intoxication of alcohol or diazepam, cerebral infarction, acute or chronic respiratory failure, and various severe shock have achieved good results as well. Since 2002, almost a hundred of production approval documents for naloxone have been issued by SFDA. During 2008 and 2009, a total of 18 manufacturers were providing naloxone products for four regions, namely Beijing, Zhejiang Province, Jilin Province and Yunnan Province in large amounts.

Although naloxone is an opioid receptor antagonist used most widely in clinic practice currently, it is inefficacious when administered orally in the form of tablets due to a significant first pass effect of hepar. Only two dosage forms, injections and sublingual tablets, are currently used in clinical practice. Meanwhile, due to significant penetration of naloxone through blood-brain barrier, it counteracts the analgesic effect of opioids while reducing the bowel dysfunction and constipation caused by chronic opioid administration in patients suffering from chronic pain.
The technology of polyethylene glycol (PEG) modification (hereinafter also referred to as PEGylation) is a new drug delivery technology developed rapidly in recent years and primarily for injection administration systems. It is a technology of linking activated PEG molecules to drug molecules or surfaces. PEGylated small molecular drugs mainly have the following advantages: (i). increased water solubility; (ii). reduced toxicity; (iii). increased circulating half-life of the drugs, reduced administration frequency, improved patient compliance, improved quality of life, and reduced treatment costs; (iv). reduced enzymolysis, and increased bioavailability; and (v). reduced penetration through blood-brain barrier, and reduced CNS side effects. Upon PEGylation of drugs, the pharmacokinetics of the drugs changes, and in turn, the pharmacodynamics thereof changes. In particular, PEG can prolong the duration in which the blood levels of the drugs are maintained at or close to target concentrations, thereby ensuring sufficient efficacy of the drugs. Currently, representative PEGylated pharmaceutical products in the international market include PEG-intron®, PEGasys®, Neulasta®, Macugen®, Neulasta®, and MICERA. So far, no PEGylated small molecular drugs have been approved for marketing in the international market, though several products, such as NKTE-102 and NKTR-118 from Nektar Therapeutics, have entered phase II or phase III clinical trials.
Our experimental group has been endeavored to researches of PEGylated small molecular drugs (related patents include Chinese Patent Nos. ZL03 8 01109.3, ZL 2004 1 0029615.3, ZL 2004 8 0005763.X, ZL 2008 1 0093688.7, ZL 02 1 07842.4, and ZL 02 1 08778.4). Our researches focus on linking PEG molecules to small molecular drugs, and the resulting products are significantly improved, having increased water solubility and reduced toxicity.
The product prepared by modifying naloxone structure with the technology of PEGylation, NKTR-118, entered phase III clinical trials (see http://www.nektar.com/pdf/pipeline/NKTR-118/pr—20110315.pdf). in March of 2011. In NKTR-118, PEG links to only one active moiety.
The object of the present invention is to overcome the defects of the existing technology, and solve the problem of conjugating multiple naloxone molecules to a single PEG molecule. In the present invention, the technology of PEGylation is employed for structural modification of naloxone, and by linking naloxone to PEG having low molecular weight, the pharmacokinetic properties of the drug are improved, the water solubility of naloxone is increased, the in vivo distribution of the drug is improved, the side effects of naloxone on CNS are reduced, the bowel dysfunction and constipation caused by chronic administration of opioids are alleviated, and injections and formulations for oral administration are developed. The experimental group, depending on its own advantages, synthesized and screened a number of PEG-naloxone derivatives. Unlike NKTR-118, in the compounds of the present invention, two or more active moieties are linked to a single PEG molecule. Therefore, the opioid receptor antagonistic activity of these compounds is superior to that of NKTR-118 of the same molecular weight.